Rapid infusion of a phospholipid emulsion attenuates the effects of endotoxaemia in horses

REASONS FOR PERFORMING STUDY: Endotoxaemia currently is associated with a poor prognosis in horses. The results of recent trials in other species indicate that phospholipid emulsions reduce the deleterious effects of endotoxin (LPS). However, in a previous study in horses, a 2 h infusion of emulsion caused an unacceptable degree of haemolysis. HYPOTHESIS: Rapid administration of a lower total dose of emulsion would reduce the effects of LPS and induce less haemolysis; the emulsion would reduce inflammatory effects of LPS in vitro. METHODS: Twelve healthy horses received an i.v. infusion either of saline or a phospholipid emulsion (100 mg/kg), followed immediately by E. coli 055:B5 LPS (30 ng/kg). Clinical parameters, haematological profiles, serum tumour necrosis factor (TNF) activity, serum lipid profiles, urine analyses and severity of haemolysis were monitored before and at selected times after LPS. Monocytes were also incubated in vitro with LPS in the presence or absence of emulsion, after which TNF and tissue factor activities were determined. RESULTS: Clinical signs of endotoxaemia were reduced in horses receiving the emulsion, including clinical score, heart rate, rectal temperature, serum TNF activity, and the characteristic leucopenic response to LPS, when compared to horses not receiving the emulsion. Three horses receiving the emulsion had none, 2 had mild and one had moderate haemolysis. There were no differences in urinalysis results and creatinine concentrations, either within the groups over time or between the groups. Serum concentrations of phosphatidylcholine, bile acids and triglycerides peaked immediately after the infusion; there were no significant changes in concentrations of nonesterified fatty acids or cholesterol. Incubation of equine monocytes with emulsion prevented LPS-induced TNF and tissue factor activities. CONCLUSIONS: Rapid administration of emulsion significantly reduced inflammatory effects of LPS in vivo and caused a clinically insignificant degree of haemolysis. The results of the in vitro studies indicate that emulsion prevents not only LPS-induced synthesis of cytokines, but also expression of membrane-associated mediators (i.e. tissue factor). POTENTIAL RELEVANCE: Rapid i.v. administration of emulsions containing phospholipids that bind endotoxin may provide a clinically useful method of treating endotoxaemia in horses.     

Evaluation of dimethyl sulphoxide effects on initial response to endotoxin in the horse

REASONS FOR PERFORMING STUDY: Endotoxaemia is one of the most severe and ubiquitous disease processes in horses. Although dimethyl sulphoxide (DMSO) is used clinically in horses, there is no study indicating its efficacy in endotoxaemic horses. HYPOTHESIS: DMSO ameliorates the clinical response to i.v. lipopolysaccharide (LPS) administration. METHODS: Eighteen horses were assigned randomly to one of 4 groups: Normosol-LPS (0.2 mug/kg bwt, i.v.); DMSO (1 g/kg bwt, i.v.)-saline; high-dose DMSO (1 g/kg bwt, i.v.)LPS; low-dose DMSO (20 mg/kg bwt, i.v.)-LPS. Horses participating in the DMSO-saline group were later assigned randomly to one of the LPS groups. Data for physical parameters, white blood cell counts, plasma TNF-alpha, and blood lactate and glucose concentrations were examined for the effect of treatment using a repeated-measures mixed-model ANOVA. A value of P<0.05 was considered significant. RESULTS: Endotoxaemia occurred in all horses receiving LPS, as indicated by the clinical score, physical parameters, haemoconcentration and leucopenia. High-dose DMSO ameliorated the effect of LPS on fever. DMSO, at either dose, but did not have a significant effect on LPS-induced changes in all other evaluated parameters. CONCLUSIONS: In this study, DMSO had minimal effects on clinical signs of induced endotoxaemia in horses. The effects were manifested by amelioration of LPS-induced fever.     

Effect of endotoxin administration on body fluid compartments in the horse

Plasma volume, extracellular fluid volume (ECFV), and total body water (TBW) were measured before and after endotoxin (Escherichia coli) administration in 6 conscious adult horses. Evan's blue dye, sodium thiocyanate, and antipyrine were the test substances used to estimate plasma volume, ECFV, and TBW, respectively. Pharmacokinetic analysis of plasma concentration vs time was used to determine changes in body fluid compartments. The pathophysiologic effects of endotoxin were monitored by clinical evaluation, blood chemical changes, and blood gas determinations. All horses became dyspneic within 15 minutes of endotoxin administration and clinical signs of colic were evident 30 to 45 minutes after endotoxin administration. After endotoxin administration, serum glucose and creatinine concentrations were significantly (P less than 0.05) elevated, and all horses became hypoxic and developed marked metabolic acidosis, and plasma volume decreased approximately 15% (P less than 0.05). A significant change in ECFV or TBW during the 300-minute experimental period was not observed.     

Effect of endotoxin administration on equine digital hemodynamics and starling forces

Using a pump-perfused extracorporeal isolated digital preparation, the effects of a 30-minute infusion of either saline solution (control) or endotoxin on equine digital hemodynamics and microvascular function were determined. Digital blood flow and arterial, venous, and capillary pressures were recorded at 15-minute intervals for 150 minutes. From these data, total vascular resistance and pre- and postcapillary resistances were calculated. Isogravimetric capillary filtration coefficient, vascular compliance, and the osmotic reflection coefficient were determined after the last hemodynamic measurements were taken. Changes in hemodynamic values of control equine digits were not observed. During the 120 minutes after infusion of endotoxin, digital blood flow decreased 43%, and total vascular resistance increased 89%. Precapillary resistance increased 122%, but postcapillary resistance did not change significantly. Changes in vascular compliance or the capillary filtration coefficient were not observed in response to either treatment. The osmotic reflection coefficient, an index of permeability, did not differ significantly between digits of the endotoxin-treated and control groups. These data indicate that the increase in vascular resistance during endotoxemia may have been attributable to arterial/arteriolar constriction and that neither the permeability nor the surface area of the exchange vasculature within the digit was significantly affected by endotoxin. Although marked alterations in vascular function are seen after administration of endotoxin, these changes do not parallel those documented in association with experimentally induced laminitis.     

Effect of oral administration of electrolyte pastes on rehydration of horses

OBJECTIVE: To determine whether the composition of electrolyte pastes formulated for oral administration influences voluntary water intake (WI) by horses recovering from furosemide-induced dehydration. ANIMALS: 6 horses. PROCEDURES: Voluntary WI, body weight, and blood and urine constituents were measured before and after induction of dehydration by furosemide administration and overnight withholding of water; these same variables also were measured during a 36-hour rehydration period. Each horse was evaluated 4 times with random application of 4 treatments (electrolyte pastes) that provided 0.5 g of KCl/kg of body weight, 0.5 g of NaCl/kg, 0.25 g of NaCl and 0.25 g of KCl/kg, or no electrolytes (control treatment). Electrolyte pastes were administered 3 times (4, 8, and 12 hours after start of the rehydration period). RESULTS: Administration of all electrolyte pastes resulted in significantly greater voluntarily WI, compared with the control treatment, and was accompanied by significantly greater recovery of body weight when NaCl was a component of the paste. Administration of NaCl and NaCl-KCl pastes tended to produce a state of transient hyperhydration; however, electrolyte administration also resulted in significantly greater urine production and electrolyte excretion during the final 24 hours of the rehydration period. Adverse effects of oral administration of hypertonic electrolyte pastes were not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of electrolyte pastes to dehydrated horses increases voluntary WI and improves rehydration during the rehydration period. Rehydration is more rapid and complete when NaCl is a component of the electrolyte paste.     

Plasma endotoxin concentration in horses: a methods study

Background: Accurate determination of plasma endotoxin concentration is critical for ex vivo and in vitro cellular and molecular studies of endotoxemia in horses. However, reports are conflicting with respect to anticoagulant, handling, and sample preparation.

Objective:

Objective: The purpose of this study was to determine the effect of blood sample fraction and handling time on measurement of endotoxin concentration in horses.

Methods:

Methods: Whole blood, anticoagulated with 3.8% (0.12 M) sodium citrate (9:1), was collected from 5 healthy horses. Whole blood (WB), platelet-rich plasma (PRP), and platelet-poor plasma (PPP) were spiked with endotoxin (2 EU/mL). Endotoxin-spiked WB samples were centrifuged immediately to generate PRP for measurement. Endotoxin concentration was subsequently measured by Limulus amebocyte assay at 0, 15, 30, 45, and 60 minutes. Assays were performed in triplicate and results were analyzed using Student's t -test, with significance set at P < .05.

Results:

Results: Mean endotoxin concentrations in 2 EU/mL-spiked WB were significantly different from those in PPP at all time points tested. Recovery of endotoxin in PRP generated from WB was significantly diminished after just 15 minutes.

Conclusion:

Conclusion: PRP generated from WB is significantly more reliable than PPP in determining endotoxin concentration ex vivo. Measurement of endotoxin in PRP generated from WB was significantly diminished after 15 min, identifying a time frame within which to process blood samples for endotoxin analysis.     

Clinical and endocrine response to repeated daily administration of endotoxin in pigs

Endotoxins of Gram-negative bacteria elicit biphasic fever, leukopenia, increased hypocalcemia, PGF_2α release, and blood-circulation shock in the mammalian body (Fredriksson 1984). The toxicity of a given endotoxin decreases after repeated endotoxin administration. This tolerance appears to arise through both non-immunological regulatory and immunological pathways. This first phase of tolerance exhibits no inter-endotoxin specificity, and appears to be caused by the lipid A portion of the endotoxin molecule. The later phase of tolerance, however, is endotoxin specific and is probably in part evoked by an immunological tolerance to the O-antigen polysaccharide chain of the endotoxin (Lindberg et al 1983). The purpose of this project was to investigate the clinical and endocrine response to repeated daily administration of endotoxin in pigs.     

Effect of butorphanol administration on cardiovascular parameters in isoflurane-anesthetized horses - a retrospective clinical evaluation.

OBJECTIVE: To determine cardiovascular responses to administration of butorphanol in isoflurane-anesthetized horses. STUDY DESIGN: Retrospective evaluation of anesthetic records. ANIMALS: Seventy-six horses anesthetized for a variety of clinical surgical procedures. METHODS: Anesthetic records of clinical equine patients anesthetized between January 1999 and December 2003 were searched. The records were reviewed for horses in which anesthesia was induced with ketamine and a benzodiazepine and maintained with isoflurane, and horses that received butorphanol intraoperatively. Exclusion criteria included horses in which the rate of infusion of an inotrope or end-tidal isoflurane concentration was changed 10 minutes before or after the butorphanol bolus. The horses were separated into two groups: group 1 horses received butorphanol at intervals as part of a balanced protocol, group 2 horses had > or = 10% increase in heart rate (HR) or blood pressure within 10 minutes prior to butorphanol administration. RESULTS: Eighty-nine butorphanol administration events matched the criteria for inclusion, 49 in group 1 and 40 in group 2. There were no significant changes after butorphanol administration in systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), and heart rate (HR) in group 1, or in end-tidal carbon dioxide concentration or hemoglobin oxygen saturation in either group. There were significant decreases in SAP (p < 0.0001), MAP (p < 0.0005), and DAP (p < 0.0008) after butorphanol administration in group 2. CONCLUSIONS AND CLINICAL RELEVANCE: The results presented here confirm that butorphanol can be administered to horses during isoflurane anesthesia without adverse effects on HR and arterial blood pressure. The results imply that butorphanol can deepen the plane of anesthesia and obtund sympathetic stimulation from a surgical procedure.     

Effect of exercise on the immune response of young and old horses.

OBJECTIVE: To compare exercise-induced immune modulation in young and older horses. ANIMALS: 6 young and 6 aged horses that were vaccinated against equine influenza virus. PROCEDURE: Venous blood samples were collected for immunologic assessment before and immediately after exercise at targeted heart rates and after exercise for determination of plasma lactate and cortisol concentrations. Mononuclear cells were assayed for lymphoproliferative responses and incubated with interleukin-2 (IL-2) to induce lymphokine-activated killer (LAK) cells. Antibodies to equine influenza virus were measured. RESULTS: Older horses had significantly lower proliferative responses to mitogens than younger horses prior to exercise. Exercise caused a significant decrease in lymphoproliferative response of younger horses, but not of older horses. Activity of LAK cells increased slightly with exercise intensity in younger horses. Cortisol concentrations increased in both groups after exercise; younger horses had higher concentrations after exercise at heart rates of 180 and 200 beats/min than those of older horses. Plasma lactate concentrations increased with exercise intensity but there were no differences between older and younger horses. Older horses had lower antibody titers to equine influenza virus than younger horses. Exercise did not affect antibody titers. CONCLUSION: Although lymphoproliferative responses and antibody titers of older horses were less than those of younger horses, older horses were more resistant to exercise-induced changes in immune function, possibly because of lower cortisol concentrations. CLINICAL RELEVANCE: Stress and aging are known to affect immune function. Older horses had reduced immune function, but were more resistant to exercise-induced immune suppression than younger horses.     

Effects of infusion of adenosine triphosphate-magnesium chloride on cardiopulmonary and clinicopathologic variables, cytokine activity, and endothelin concentration in horses administered a low dose of endotoxin

OBJECTIVE: To evaluate systemic effects of i.v. infusion of ATP-MgCl2 subsequent to infusion of a low dose of endotoxin in horses. ANIMALS: 12 adult horses. PROCEDURE: Horses were administered endotoxin (lipopolysaccharide [LPS]) or saline (0.9% NaCl) solution i.v., during a 30-minute period. Immediately thereafter, horses in each group were infused i.v. with ATP-MgCl2 or saline solution. Two weeks later, horses were administered the opposite solution (LPS or saline solution), but it was followed by the same infusion as 2 weeks previously (ie, ATP-MgCl2 or saline solution). Cardiopulmonary and clinicopathologic variables, cytokine activity, and endothelin (ET) concentrations were recorded. RESULTS: IV infusion of ATP-MgCl2 after administration of a low dose of endotoxin failed to attenuate the cardiopulmonary, clinicopathologic, and cytokine alterations that develop secondary to endotoxin exposure. The combination of LPS and ATP-MgCl2 potentiated pulmonary hypertension, leukopenia, and neutropenia when compared with the combination of LPS and saline solution. The combination of LPS and ATP-MgCl2 resulted in thrombocytopenia. Endothelin concentration was increased in jugular venous and pulmonary arterial plasma in horses receiving LPS and ATP-MgCl2. Similar increases were not observed with LPS and saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of ATP-MgCl2 did not protect horses from systemic effects of experimentally induced endotoxemia. Furthermore, the use of ATP-MgCl2 during endotoxemia may worsen the cardiopulmonary and clinicopathologic status of affected horses. Because ATP and other adenine nucleotides are released from cells during shock, their potential role in the development of hemodynamic derangements, leukocyte adherence, and coagulopathies during endotoxemic episodes warrants further investigation.     

Effect of dimethylglycine on antibody response to influenza vaccination in horses

A double blind study evaluating the humoral response to influenza vaccination was studied in 20 age and sex matched mature horses. The horses had been immunized previously once or twice yearly but none had been vaccinated or was known to have been exposed to influenza within the preceding six months. Horses received either placebo or dimethylglycine (750 mg orally twice daily) from Days 1 through 45 and were vaccinated intramuscularly on Day 15 with a killed influenza virus vaccine containing both A₁ and A₂ serotypes. Serum hemagglutination titers were determined by 2 independent laboratories on identical serum samples drawn on Days 1, 15, and 45. No significant difference was found between the placebo and dimethylglycine treated group in the development of either A₁ or A₂ antibody titers following vaccination.     

Responses of horses to acepromazine maleate administered orally in a paste

The effects of acepromazine maleate (ACP), given orally in a paste form, were examined in six standard-bred geldings over a 12 hour period. Three dose rates, zero (placebo paste), 0.13 mg kg-1 and 0.26 mg kg-1, given before or after feeding, were investigated. The data were divided into two sampling periods for analysis, one from zero to 120 minutes and the other from four to 12 hours. Sedation was assessed by a score (TS score) based on general appearance, anal sphincter relaxation and penile protrusion. This TS score was significantly elevated 40 minutes after dosing with ACP, irrespective of whether the horses had been fed or not. Dose rate had no significant effect on TS in the zero to 120 minute sampling period, but the TS score was significantly (P less than 0.01) higher at the higher dose rate in the four to 12 hour period. At both dose rates, the TS scores were still significantly higher than their pretreatment values 12 hours after dosing. Systolic blood pressure (SBP), measured indirectly from the coccygeal artery, haematocrit (PCV) and total plasma protein concentration (TPP) were also examined. ACP caused significant falls in SBP and PCV, but the effect was complicated by feeding. ACP given after feeding had a reduced effect on SBP and PCV. Feeding appeared to cause a rise then a fall in PCV and TPP which was superimposed upon the fall caused by ACP. There was no difference between the two dose rates of ACP on SBP and PCV.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of continuous or intermittent lipopolysaccharide administration for 48 hours on the systemic inflammatory response in horses

Objective-To determine whether the method of lipopolysaccharide (LPS) administration (intermittent vs continuous) affects the magnitude and duration of the systemic inflammatory response in horses and whether prolonged (48 hours) endotoxemia induces laminitis. Animals-12 healthy adult horses (10 mares and 2 geldings). Procedures-Horses were randomly assigned to receive LPS (total dose, 80 μg; n = 4) or saline (0.9% NaCl) solution (80 mL/h; 4) via constant rate infusion or 8 bolus IV injections of LPS (10 μg, q 6 h;4) during a 48-hour period. Physical examinations were performed every 4 hours, inflammatory cytokine gene expression was determined for blood samples obtained every 8 hours, and IV glucose tolerance tests were performed. Results-All LPS-treated horses had signs of depression and mild colic; those signs abated as the study progressed. Administration of LPS increased expression of interleukin-1β, interleukin-6, and interleukin-8, but results were not significantly different between LPS treatment groups. Cytokine expression was significantly higher on the first day versus the second day of LPS treatment. Interleukin-1β expression was positively correlated with rectal temperature and expression of other cytokines. Glucose and insulin dynamics for both LPS groups combined did not differ significantly from those of the saline solution group. Signs of laminitis were not detected in any of the horses. Conclusions and Clinical Relevance-Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses.     

Effect of chronic clenbuterol administration and exercise training on immune function in horses

Effects of longitudinal exercise training and acute intensive exercise (simulated race test) on immune function have not been reported in horses. Clenbuterol, a beta2-adrenergic agonist, is used to manage inflammatory airway disease in horses. This study investigated the interaction of 8 wk of exercise training with or without 12 wk of clenbuterol administration in horses. Twenty-three untrained standardbred mares (10 +/- 3 yr, Mean +/- SE) were used and divided into four experimental groups. Horses given clenbuterol plus exercise (CLENEX; n = 6) and clenbuterol alone (CLEN; n = 6) received 2.4 microg/kg BW of clenbuterol twice daily (in an average volume of 20 mL) on a schedule of 5 d on and 2 d off for 12 wk. The CLENEX group was also aerobically trained 3 d/wk. Mares given exercise alone (EX; n = 5) were aerobically trained for 3 d/wk, and the control group (CON; n = 6) remained sedentary. Both EX and CON horses were administered similar volumes (approximately 20 mL) of molasses twice daily. A simulated race test (SRT) resulted in an elevation in lymphocyte number postexercise (P < 0.05). There was no significant difference after acute exercise in either monocyte or granulocyte number. Acute exercise resulted in a decrease (P < 0.05) in the percentage of CD4+ and an increase (P < 0.05) in the percentage of CD8+ cells. The SRT resulted in a decreased lymphoproliferative response to pokeweed mitogen (P < 0.05). A SRT had no effect on antibody production in response to equine influenza vaccine. The EX group demonstrated greater cortisol concentrations at rest and at all other time points postexercise after completing the training regimen compared with CLENEX horses (P < 0.05). Preexercise (SRT) peripheral blood monocyte number was lower in CLENEX horses than in other treatment groups (P < 0.05). Clenbuterol and exercise training did not significantly affect post-SRT changes in leukocyte numbers. Exercise training resulted in a decrease (P < 0.05) in the percentage of CD8+ cells post-SRT compared with other groups, but the percentage of CD4+ cells was not altered by either clenbuterol or exercise conditioning. Lymphocyte proliferative response was not affected by clenbuterol or exercise treatment. Horses demonstrated responses to bouts of acute exercise as noted with other species, namely humans and rodents.     

Re-evaluation of the pharmacokinetics of xylazine administered to Thoroughbred horses

Xylazine is widely used worldwide as a short-acting sedative in general equine and racing practice. In the UK, although it has a legitimate use during training, equine anti-doping rules state it is a prohibited substance on race day. The aim of the study was to produce a detection time (DT) to better inform European veterinary surgeons so that xylazine can be used appropriately under regulatory rules. Previous publications have various limitations pertaining to analysis method, particularly for plasma and limited length of time of sample collection. In this study, pharmacokinetic data were produced for xylazine and 4-OH-xylazine in equine urine and plasma following a single intravenous xylazine dose of 0.4 mg/kg to six Thoroughbred horses. Pharmacokinetic parameters were generated from a 3-compartmental model with clearance = 15.8 ± 4.88 ml min^-1 kg^-1, Vss = 1.44 ± 0.38 L/kg, terminal half-life = 29.8 ± 12.7 hr and a DT determined at 71 hr for the administration of xylazine (Chanazine^®) in plasma and urine. Urine screening should aim to detect the 4-OH-xylazine metabolite, which can act as an indicator for the xylazine plasma concentration. A DT of 72 hr has been agreed by the European Horserace Scientific Liaison Committee, to be implemented in June 2019.     

Effect of intermittent oral administration of ponazuril on experimental Sarcocystis neurona infection of horses

OBJECTIVE: To evaluate the effect of intermittent oral administration of ponazuril on immunoconversion against Sarcocystis neurona in horses inoculated intragastrically with S neurona sporocysts. ANIMALS: 20 healthy horses that were seronegative for S neurona-specific IgG. PROCEDURES: 5 control horses were neither inoculated with sporocysts nor treated. Other horses (5 horses/group) each received 612,500 S neurona sporocysts via nasogastric tube (day 0) and were not treated or were administered ponazuril (20 mg/kg, PO) every 7 days (beginning on day 5) or every 14 days (beginning on day 12) for 12 weeks. Blood and CSF samples were collected on day - 1 and then every 14 days after challenge for western blot assessment of immunoconversion. Clinical signs of equine protozoal myeloencephalitis (EPM) were monitored, and tissues were examined histologically after euthanasia. Results: Sera from all challenged horses yielded positive western blot results within 56 days. Immunoconversion in CSF was detected in only 2 of 5 horses that were treated weekly; all other challenged horses immunoconverted within 84 days. Weekly administration of ponazuril significantly reduced the antibody response against the S neurona 17-kd antigen in CSF. Neurologic signs consistent with EPM did not develop in any group; likewise, histologic examination of CNS tissue did not reveal protozoa or consistent degenerative or inflammatory changes. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of ponazuril every 7 days, but not every 14 days, significantly decreased intrathecal anti-S neurona antibody responses in horses inoculated with S neurona sporocysts. Protocols involving intermittent administration of ponazuril may have application in prevention of EPM.     

The pharmacokinetics of dexmedetomidine administered as a constant rate infusion in horses

Dexmedetomidine, the most selective α₂‐adrenoceptor agonist in clinical use, is increasingly being used in both conscious and anaesthetized horses; however, the pharmacokinetics and sedative effects of this drug administered alone as an infusion are not previously described in horses. Seven horses received an infusion of 8 μg dexmedetomidine/kg/h for 150 min, venous blood samples were collected, and dexmedetomidine concentrations were assayed using liquid chromatography‐mass spectrometry (LC/MS) and analyzed using noncompartmental pharmacokinetic analysis. Sedation was scored as the distance from the lower lip of the horse to the ground measured in centimetre. The harmonic mean (SD) plasma elimination half‐life (Lambda z half‐life) for dexmedetomidine was 20.9 (5.1) min, clearance (Cl) was 0.3 (0.20) L/min/kg, and volume of distribution at steady‐state (Vd_ss) was 13.7 (7.9) L/kg. There was a considerable individual variation in the concentration of dexmedetomidine vs. time profile. The level of sedation covaried with the plasma concentration of dexmedetomidine. This implies that for clinical use of dexmedetomidine constant rate infusion in conscious horses, infusion rates can be easily adjusted to effect, and this is preferable to an infusion at a predetermined value.